Research Summary

The YCAAD research program focuses on understanding the mediators and mechanisms underlying the development of asthma and other airways diseases with a focus on patients with more severe disease. Our goals are to understand the pathogenesis of asthma, develop novel clinical tests to enhance the treatment of patients with asthma, and ultimately develop novel treatments and potential cures for asthma.

Specialized Terms: Pathogenesis of airway diseases with a focus on asthma and asthma severity; Chitinases in the development and severity of asthma; Expression and genotype-phenotype relationships of novel inflammatory molecules

Extensive Research Description

Yale Center for Asthma and Airways Disease (YCAAD) Research Program

Yale-New Haven Hospital is the largest referral center in the state and YCAAD is the only dedicated adult asthma center in the region. This active, rapidly growing center receives over 3000 visits a year and is the hub of the clinical/translational research program at Yale. Dr. Geoffrey Chupp, has directed YCAAD and developed a clinical research protocol, The Mechanisms and Mediators of Asthma and COPD (HIC 12268), that has recruited over 400 airway disease subjects to donate specimens to the YCAAD sample repository and participate in YCAAD research activities. The evolution of this research protocol, dovetailed with the clinical program, is a unique system that efficiently recruits subjects into clinical study protocols. These subjects have been recruited in YCAAD and are drawn from a large population of patients that continue to visit the center on a regular basis for long term care of their asthma. This allows for repeat sampling, thus enabling our active pursuit of longitudinal studies. In addition, many of these patients are seen during exacerbations in YCAAD or Yale-New Haven Hospital where exacerbation samples can be taken. From this protocol has grown a large sample repository of clinical and physiologic data, DNA, plasma and lung specimens from asthmatics that are stable or flaring (including the intensive care unit). All of this data is uploaded into a web-based database so that information enters the system in real-time.

YKL-40 Expression is Elevated in the Circulation and Lung of Severe Asthmatics

Once we had established the YCAAD research protocol and recruited an adequate number of patients, we began to search for clinically-practical biomarkers for asthma, focusing on the chitinase-like protein, YKL-40, based on the fact that its murine homologue is induced by interleukin (IL)-13 and it is measurable in the serum. We hypothesized that YKL-40 expression would be increased in asthmatics compared to normal individuals. We also hypothesized, although asthma is traditionally considered an organ-specific disease, that YKL-40 levels in the peripheral circulation would discriminate asthmatic severity. YKL-40 was readily appreciated in the serum from normal volunteers and was significantly higher in the serum from asthmatics [median (interquartile range) 58.3 ng/ml (40.0-73.3) versus 69.7 (40.0-107.1), P=0.02]. Importantly, YKL-40 levels increased with disease severity, with the highest levels observed in refractory asthmatics, compared to moderate and mild asthmatics, respectively (P for trend = 0.003). The median (interquartile range) YKL-40 level in mild asthmatics was 49.11 ng/ml (36.7-94.2), 68.43 ng/ml (38.0-88.0) in moderate asthmatics, and 77.0 (44.6-158.4) in severe asthmatics. Based on the findings above, it was clear that circulating YKL-40 levels are elevated in asthmatics and, importantly, in severe asthmatics. The levels of YKL-40 also correlated with the expression in the lung and physiologic and pathologic measurements of airway remodeling. This suggested an important role for YKL-40 in the pathobiology of asthma, however, it remained unclear where YKL-40 played its part in the causal pathway and/or does it play a role in modulation of the asthmatic inflammatory response? To address this critical question in humans we hypothesized that genetic variation in the YKL-40 gene (CHI3L1) would influence circulating YKL-40 levels and would be associated with asthma. We thus pursued studies in collaboration with Dr. Carole Ober at the University of Chicago. In these studies, three additional asthma populations were examined, a well characterized founder population of European descent--the Hutterites (a related 13-generation, 1,623-person pedigree), 3 outbred Caucasian populations from the Childhood Origins of ASThma (COAST) birth cohort study, and 2 outbred asthma case-control populations from Freiberg Germany, and Chicago. These studies confirmed our findings in the YCAAD cohort and demonstrated that a polymorphism in the core promoter region of the CHI3L1 gene is associated with YKL-40 levels and with asthma, lung function and bronchial hyperresponsiveness. Now that we have confirmed that CHI3L1 is important in the pathogenesis of asthma, through the molecular phenotyping of lung disease grant Dr. Chupp is the Principle Investigator of, we will begin to dissected the pathobiologic differences in gene expression between individuals with different CHI3L1/YKL-40 genotypes and phenotypes and the impact that these changes have on the risk of asthma and asthma severity. Below is a brief description of the recently awarded phenotyping grant that will study 200 asthmatics for the next two years and will simultaneously measure genome-wide expression of genes in the blood and induced sputum using novel techniques developed in Dr. Chupp’s lab.

Molecular Phenotpying in Asthma Severity and role of Chitinase-3-Like-1 and YKL-40 Genotypes/Phenotypes (RO1-08-006)

We have developed a detailed clinical protocol and will be bringing patients into YCAAD for simultaneous blood and induced sputum sampling with a goal of furthering our understanding of severe asthma and the role of chitinases in asthma. Thus far, the human studies showed that YKL-40 is expressed in exaggerated quantities in the serum of asthma and correlates positively with asthma severity and airway remodeling, but inversely with lung function in multiple asthma populations. The genetic studies demonstrated that YKL-40 levels are associated with a functional polymorphism in the promoter of the CHI3L1 gene and with asthma status, bronchial hyperresponsiveness, and inversely with lung function. Therefore, YKL-40 is not only elevated in asthma, but also appears to part of the pathogenesis of asthma, at least in some patients. Another important observation we have made from these data is that the rs4950928 CC genotype is associated with the highest levels of circulating YKL-40 and nearly all these individuals are severe asthmatics. Furthermore, the frequency of the CC genotype increases with greater asthma severity. Lastly, using a strategy outlined in this proposal to evaluate gene transcription in the circulation, we have found (consistent with all our other results) that CHI3L1 gene expression is elevated in peripheral blood cells in asthmatics compared to controls and that GWAS analysis of individuals with high expression levels of CHI3L1 have identified a number of novel genetic associations will be investigated/validated with collaborators in other asthma populations. We have also demonstrated that relatively small changes in protein and gene expression in the circulation, while at first glance may seem unimportant biologically, when properly validated can identify novel molecules related to asthma pathogenesis. We believe that examining asthma severity using a similar strategy (relative to rs4950928 genotype, YKL-40 levels) will define unique expression profiles, molecules, and polymorphisms that will define specific phenotypes of asthma severity. Asthma Severity YKL-40 CHI3L1 gene.1. Molecular Phenotyping of Asthma Severity: In this project we are characterizing 200 asthmatics and collecting induced sputum and peripheral blood for genome-wide expression profiling to identify gene profiles that associated with asthma severity and common to both the peripheral blood and lung.

2. Gene expression profiles associated with CHI3L1 genotypes and YKL-40 levels in asthma: From the population described above, we are determining the biologic pathways associated with genetic polymorphisms we have determined are associated with asthma and asthma severity.

3.Expression profiles associated with responsiveness to Xolair. Using the profile we have developed for the gene expression study, we will determine the gene profiles that altered in response to treatment with Xolair.

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